A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study
Date
2007
DOI
Authors
Kathiresan, Sekar
Manning, Alisa
Demissie, Serkalem
D'Agostino, Ralph B.
Surti, Aarti
Guiducci, Candace
Gianniny, Lauren
Burtt, Noel P.
Melander, Olle
Orho-Melander, Marju
Version
OA Version
Citation
2007. "A genome-wide association study for blood lipid phenotypes in
the Framingham Heart Study," BMC Medical Genetics. vol. 8 issue. Suppl 1 .
Abstract
BACKGROUND:Blood lipid levels including low-density lipoprotein
cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG)
are highly heritable. Genome-wide association is a promising approach to map genetic loci
related to these heritable phenotypes.METHODS:In 1087 Framingham Heart Study Offspring
cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses
(Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG
were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald
formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a
~30 year span were the primary phenotypes. We used generalized estimating equations (GEE),
family-based association tests (FBAT) and variance components linkage to investigate the
relationships between SNPs (on autosomes, with minor allele frequency [greater than or equal
to]10%, genotypic call rate [greater than or equal to]80%, and Hardy-Weinberg equilibrium p
[greater than or equal to] 0.001) and multivariable-adjusted residuals. We pursued a
three-stage replication strategy of the GEE association results with 287 SNPs (P <
0.001 in Stage I) tested in Stage II (n ~1450 individuals) and 40 SNPs (P < 0.001 in
joint analysis of Stages I and II) tested in Stage III (n~6650
individuals).RESULTS:Long-term averages of LDL-C, HDL-C, and TG were highly heritable (h2 =
0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the
phenotypes, two SNPs had p < 10-5 in GEE results for LDL-C, four for HDL-C, and one
for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p
< 10-4 ranged from 13 to 18 and with p < 10-3, from 94 to 149. Some results
confirmed previously reported associations with candidate genes including variation in the
lipoprotein lipase gene (LPL) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002
for TG). The full set of GEE, FBAT and linkage results are posted at the database of
Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing
statistical evidence for association (i.e., combined P < 10-5 across all three
stages) between any of the tested SNPs and lipid phenotypes.CONCLUSION:Using a 100K
genome-wide scan, we have generated a set of putative associations for common sequence
variants and lipid phenotypes. Validation of selected hypotheses in additional samples did
not identify any new loci underlying variability in blood lipids. Lack of replication may be
due to inadequate statistical power to detect modest quantitative trait locus effects (i.e.,
< 1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS
in FHS using a denser genome-wide genotyping platform and a better-powered replication
strategy may identify novel loci underlying blood lipids.